Crystalline forms of compounds are often important when the compound is used in pharmaceutical applications. Compared with an amorphous solid, the solid physical properties of a crystalline compound can be markedly different, affecting its suitability for pharmaceutical use.
For example, different forms of a crystalline compound, including polymorphs and solvates, can incorporate different types and/or different amounts of impurities. Different solid forms of a compound can also vary in chemical stability when exposed to different environmental stressors such as heat and/or water.
Ceftolozane is a cephalosporin antibacterial agent, also referred to as CXA-101, FR264205, or by chemical names such as (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate. Ceftolozane sulfate is a pharmaceutically acceptable ceftolozane salt of compound (VI) (FIG. 1A) that can be formulated for intravenous administration or infusion.

Ceftolozane can be obtained using methods described in U.S. Pat. Nos. 7,129,232 and 7,192,943, as well as Toda et al., “Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205,” Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008), each of which are incorporated herein by reference in their entirety. An important intermediate in the known syntheses of ceftolozane is compound (III) (also referred to herein as “TATD-CLE”).

The published reaction to make compound (III) involves an isolation using solvents such as, for example, diisopropyl ether. However, this is not a preferred process because diisopropyl ether has significant vapor pressure at room temperature, is highly flammable and has the potential to form peroxides upon storage.
Given the multi-step synthesis of ceftolozane and its commercial importance, there is a need to develop new approaches for each of the individual reaction steps in the synthesis of ceftolozane, such as the synthesis of new forms of compound (III), to increase reaction yields, safety, and overall efficiency in the synthetic process.